Search Results (146)

Myotonic dystrophy type 1 (DM1) results from the toxicity of RNA produced from the mutant allele of the DMPK gene. The mechanism by which the toxic RNA causes muscular dystrophy in DM1 is unknown. Dystrophy in DM1 is associated with defective muscle regeneration and repair. Here, we used the BaCl₂-induced damage model of muscle injury to study muscle regeneration in the HSALR mouse model of DM1. We have previously shown delayed muscle regeneration and deleterious effects on satellite cell numbers in another mouse model of RNA toxicity using similar experimental approaches. We found that HSALR mice show no apparent deleterious effects on satellite cell number or early markers of muscle regeneration. Further analysis at later time points after damage showed increased numbers of internal nuclei as compared to control mice undergoing the same protocol. Muscle fiber type analysis using immunostaining for type IIA and IIB fibers identified a switch to slower fibers (increased fraction of IIA and reduced fraction of IIB fibers) after regeneration in HSALR mice as compared to regenerated muscle from wildtype mice. Full article

Cisplatin (CIS) is a widely used chemotherapeutic agent known for its efficacy; however, it induces several adverse effects, most notably cachexia, which is characterized by progressive loss of skeletal muscle mass, weakness, and reduced body weight. N-acetylcysteine (NAC) a compound with antioxidants properties, has been shown to mitigate CIS-induced neurotoxicity in experimental models. This study aimed to investigate the myoprotective effects of NAC during CIS treatment and explore the redox and molecular mechanisms involved in this response. For this, female Wistar rats were divided into four experimental groups: Control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p for 5 days), and NAC + CIS (NAC for 8 days, with CIS administered from day 4 onward). After treatment, muscle strength, redox status, mitochondrial biogenesis, expression of myogenic microRNAs and morphological changes were evaluated. CIS treatment caused muscle atrophy, decreased GSH/GSSG ratio, impaired cellular function, increased lipid peroxidation and altered antioxidant enzymes activity. These effects were mitigated by NAC coadministration. CIS also reduced the mtDNA/nDNA ratio; however, NAC treatment tended to increase TFAM and PGC-1α expression levels. Furthermore, CIS suppressed the expression of muscular miR-1-3p, miR-133a-3p and miR-206-3p, while NAC restored their levels when co-administered with CIS. These findings suggest that NAC may serve as a promising adjuvant therapeutic strategy to counteract CIS-induced myotoxicity through redox regulation and modulation of molecular pathways related to muscle integrity and regeneration. Full article

Sleep is a fundamental biological process in athletes, indispensable for tissue regeneration, exercise adaptation, and injury prevention. Disruptions in sleep architecture and duration have been consistently associated with diminished physical performance and adverse health outcomes, impairing muscular strength, power output, and endurance capacity, and concurrently compromising cognitive function. On a physiological level, insufficient sleep disrupts endocrine homeostasis, elevating cortisol levels and reducing anabolic hormones such as testosterone and growth hormone. At the molecular level, sleep loss promotes the upregulation of pro-apoptotic gene expression and exacerbates pro-inflammatory signalling pathways. Optimal sleep duration and quality represent a critical “regenerative window”, essential for enhancing athletic performance and safeguarding physiological resilience. Ensuring adequate sleep among athletes can be effectively achieved through educational, behavioural, and nutritional interventions outlined in this review. Full article

Counteracting neurodegenerative diseases (NDs) presents a multifaceted challenge in the aging societies of Western countries. Each year, millions of people worldwide are affected by such ailments as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS), spinal cord injury, ischemic stroke, motor neuron disease, spinal muscular atrophy, spinocerebellar ataxia, and amyotrophic lateral sclerosis (ALS). Advancements in modern biomaterial technologies present substantial opportunities for the field of regenerative medicine. Nevertheless, limitations arise from the requirement that biomaterial design be tailored to the specific biological parameters of the target cell types with which they are intended to interact. Such an opportunity creates nanomaterials involving nanoparticles. The surface chemistry of nanoparticles, especially when functionalized with bioactive agents, enhances biocompatibility and facilitates interactions with nervous cells. Herein, we review contemporary strategies in the application of biomaterials for nerve regeneration, with particular emphasis on nanomaterials and biocompatible polyelectrolyte layers, which the authors identify as having the most significant potential to drive transformative advances in regenerative medicine in the near future. Full article

Skeletal muscle pathologies, including sarcopenia, inflammatory myopathies, and various muscular dystrophies, are strongly influenced by chronic low-grade inflammation and impaired proteostasis. Immunoproteasomes (IMPs), inducible proteolytic complexes activated by pro-inflammatory cytokines, are emerging as regulators linking immune signaling to protein quality control. Evidence suggests that IMPs have paradoxical, context-dependent roles in skeletal muscle. On one hand, they can support proteostasis and muscle regeneration under stress; on the other, persistent activation may sustain cytokine production, antigen presentation, and maladaptive immune–muscle interactions, promoting chronic inflammation and muscle wasting. Selective IMP inhibitors, such as ONX 0914 and KZR-616, display potent anti-inflammatory effects in preclinical models of autoimmune myositis and muscle atrophy. Yet, their use in skeletal muscle pathologies is controversial; while inhibition may dampen harmful immune activation, it could also impair muscle repair and proteostasis. This review summarizes current findings, highlights key contradictions, and explores unresolved questions about the role of IMPs in skeletal muscle pathologies. We emphasize the need for a deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology and strategies combining selective inhibitors to enhance therapeutic efficacy while minimizing adverse effects. IMPs thus represent both a promising and potentially risky therapeutic target, with outcomes highly dependent on disease context. Full article

Endothelial function plays a key role in tissue repair. Reactive Oxygen Species (ROS) production impairs tissue renewal and homeostasis. Complex Magnetic Fields (CMFs) have been attracting attention as a non-invasive tool to promote tissue regeneration, especially through angiogenic stimulation. The present study aims to investigate CMF effect in an in vitro model of oxidative stress-stimulated Endothelial Cells (ECs). Cells were pre-treated with H₂O₂ to mimic an oxidative environment, followed by the application of three CMF programs repeated in two experimental sets: two consecutive cycles (two cycles) or two cycles spaced 24 h apart (T0+T24). Flow cytometry investigation shows that both CMF applications reduce ROS production, presumably promoting SODs proteins expression. Specifically, two cycles affect mitochondrial SOD-2 expression, which may promote cellular turnover by upregulating pro-apoptotic proteins, leading to mild cell death balanced with increased cell viability. T0+T24 application promotes cytosolic SOD-1 expression, which may influence the expression and release of antioxidant molecules, as evidenced by the increased protein levels of Akt/Nrf2 and the overall antioxidant activity measured post-treatment. In conclusion, ROS-induced EC dysfunction can be reverted by CMF application: 2 cycles could be applied when cellular renewal is required (such as in pathological wounds) while T0+T24 could be useful when an antioxidant and anti-inflammatory effect is needed (e.g., in edema or muscular lesions). Full article

Monocytes/macrophages promote the repair of acutely injured muscle while contributing to dystrophic changes in chronically injured muscle in Duchenne muscular dystrophy (DMD) patients and animal models including mdx and mdx^5cv mice. To elucidate the molecular mechanisms underlying this functional difference, we compared the transcriptomes of intramuscular monocytes/macrophages from wild-typed (WT) uninjured muscles, WT acutely injured muscles, and mdx^5cv dystrophic muscles, using single cell-based RNA sequencing (scRNA-seq) analysis. Our study identified multiple transcriptomically diverse monocyte/macrophage subclusters, which appear to be induced by the intramuscular microenvironment. They expressed feature genes differentially involved in muscle inflammation, regeneration, and extracellular matrix (ECM) remodeling, but none of them conform to strict M1 or M2 activation. The Gpnmb⁺Spp1⁺ macrophage subcluster, an injury-associated subcluster that features the signature genes of reported scar-associated macrophages (SAMs) involved in ECM remodeling and fibrosis, is present transiently in acutely injured muscle and persistently in chronically injured dystrophic muscle, along with the persistence of monocytes. Our findings suggest that the persistent monocyte/macrophage infiltration and activation induced by continuous injury may underlie the pathogenic roles of macrophages in mdx^5cv muscles. Controlling muscle injury and subsequent macrophage infiltration and activation may be important to the treatment of DMD. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive disease that degeneratively damages both upper and lower motor neurons, eventually resulting in muscular paralysis and death. Although ALS is broad in scope and commonly thought of as a motor neuron disease, more active research sheds light on the that role skeletal muscle plays in the development and progression of the disease. Muscle tissue in ALS patients and in animal models demonstrates severe regenerative deficits, including impaired myogenesis and impaired myoblast fusion. In ALS, muscle stem cells, known as satellite cells, show poor performance in activation, proliferation, and differentiation and thus contribute to ALS muscle wasting. Moreover, the pathological tissue environment that inhibits myoblast fusion is made up of proinflammatory cytokines, oxidative stress, and a lack of trophic signals from the neuromuscular junction, which greatly disrupts homeostatic regulation. It is likely that skeletal muscle is instead a dynamic player, fueling neuromuscular degeneration as opposed to a passive responder to denervation. One must appreciate the cellular and molecular changes that complicate muscle regeneration in ALS for effective treatment to be developed, permitting simultaneous interventions with both muscle and neurons. Full article

Background: Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs) are skeletal muscle stem cells that play an important role in adult muscle maintenance and regeneration. The absence or mutation of dystrophin in DMD is hypothesized to impair SC asymmetric division, leading to cell cycle arrest. Methods: To overcome the limited availability of biopsies from DMD patients, we used our 3D skeletal muscle organoid (SMO) system, which delivers a stable population of myogenic progenitors (MPs) in dormant, activated, and committed stages, to perform SMO cultures using three DMD patient-derived iPSC lines. Results: The results of scRNA-seq analysis of three DMD SMO cultures versus two healthy, non-isogenic, SMO cultures indicate reduced MP populations with constant activation and differentiation, trending toward embryonic and immature myotubes. Mapping our data onto the human myogenic reference atlas, together with primary SC scRNA-seq data, indicated a more immature developmental stage of DMD organoid-derived MPs. DMD fibro-adipogenic progenitors (FAPs) appear to be activated in SMOs. Conclusions: Our organoid system provides a promising model for studying muscular dystrophies in vitro, especially in the case of early developmental onset, and a methodology for overcoming the bottleneck of limited patient material for skeletal muscle disease modeling. Full article

Duchenne muscular dystrophy (DMD) manifests as a hereditary condition that diminishes muscular strength through the progressive degeneration of structural muscle tissue, which is brought about by deficiencies in the dystrophin protein required for the integrity of muscle cells. DMD is among four different types of dystrophinopathy disorders. Current studies have established that long non-coding RNAs (lncRNAs) play a significant role in determining the trajectory and overall prognosis of chronic musculoskeletal conditions. LncRNAs are different in terms of their lengths, production mechanisms, and operational modes, but they do not produce proteins, as their primary activity is the regulation of gene expression. This research synthesizes current literature on the role of lncRNAs in the regulation of myogenesis with a specific focus on certain lncRNAs leading to DMD increments or suppressing muscle biological functions. LncRNAs modulate skeletal myogenesis gene expression, yet pathological lncRNA function is linked to various muscular diseases. Some lncRNAs directly control genes or indirectly control miRNAs with positive or negative effects on muscle cells or the development of DMD. The research findings have significantly advanced our knowledge about the regulatory function of lncRNAs on muscle growth and regeneration processes and DMD diseases. Full article

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, which can result in several muscular complications, including sarcopenia, the loss of muscle mass, and impaired muscle function. Recently, postbiotics derived from lactic bacteria, such as Lactobacillus and Bifidobacterium, have emerged as potential therapeutic modulators for these complications. Postbiotics are bioactive metabolites, such as short-chain fatty acids (SCFAs), antimicrobial peptides, and other compounds produced by microorganisms during fermentation, which have anti-inflammatory, antioxidant, and metabolic regulatory effects. These metabolites are important due to their potential to positively influence muscle health in patients with IBD, mainly by reducing systemic and local inflammation, improving gut microbiota, and modulating muscle metabolism. Studies suggest that these postbiotics may help minimize muscle degradation and promote muscle tissue regeneration, assisting in the prevention or management of IBD-associated sarcopenia. Despite the promising results, challenges remain, such as variability in postbiotic production and the need for further clinical studies to establish clear therapeutic guidelines. This review article explores the mechanisms of action of postbiotics derived from lactic acid bacteria and their potential applications in the treatment of muscle complications in patients with IBD, highlighting future therapeutic perspectives. Full article

Recent studies on myogenic satellite cells (SCs) in Duchenne muscular dystrophy (DMD) documented altered division capacities and impaired regeneration potential of SCs in DMD patients and animal models. It remains unknown, however, if SC-intrinsic effects trigger these deficiencies at pre-contractile stages of myogenesis rather than resulting from the pathologic environment. In this study, we isolated SCs from a porcine DMD model and age-matched wild-type (WT) piglets for comprehensive analysis. Using immunofluorescence, differentiation assays, traction force microscopy (TFM), RNA-seq, and label-free proteomic measurements, SCs behavior was characterized, and molecular changes were investigated. TFM revealed significantly higher average traction forces in DMD than WT SCs (90.4 ± 10.5 Pa vs. 66.9 ± 8.9 Pa; p = 0.0018). We identified 1390 differentially expressed genes and 1261 proteins with altered abundance in DMD vs. WT SCs. Dysregulated pathways uncovered by gene ontology (GO) enrichment analysis included sarcomere organization, focal adhesion, and response to hypoxia. Multi-omics factor analysis (MOFA) integrating transcriptomic and proteomic data, identified five factors accounting for the observed variance with an overall higher contribution of the transcriptomic data. Our findings suggest that SC impairments result from their inherent genetic abnormality rather than from environmental influences. The observed biological changes are intrinsic and not reactive to the pathological surrounding of DMD muscle. Full article

Peripheral nerve injuries, caused by trauma or iatrogenic damage, often lead to permanent disabilities with limited effectiveness of current therapeutic treatments. This has driven the growing interest toward natural bioactive molecules, including ursolic acid (UA). Literature studies have shown that white grape pomace oleolyte (WGPO), a natural source of UA, is a promising candidate for promoting peripheral nerve regeneration. Considering that many neurological injuries involve compression or partial damage, the present study examined the effects of WGPO on peripheral neuropathy using a neuropathic pain mouse model. Briefly, 14 days after starting the WGPO-enriched diet, mice underwent cuffing of the right sciatic nerve to induce nerve injury and inflammation. At sacrifice, the WGPO-fed mice exhibited reduced muscle atrophy, as indicated by a greater number and larger diameter of muscle fibers, along with decreased expression of Atrogin-1 and Murf-1, compared with the injured control-diet group. To determine the functional impact of the WGPO treatment, the WGPO-supplemented group was compared with a control group receiving only sunflower oil, evaluating exercise performance post-cuffing via a treadmill test. Mice on the WGPO diet exhibited improved physical performance and a significantly lower expression of pro-inflammatory interleukins than controls. Our findings suggest WGPO as a promising candidate for managing peripheral neuropathy and related muscular impairments. Full article

Double homeobox (DUX) genes are key embryonic regulators that are silenced after the early cleavage stages of embryogenesis. Aberrant expression of DUX4 in skeletal muscle is linked to facioscapulohumeral muscular dystrophy (FSHD). A recent study reported that Dux, the murine ortholog of DUX4, contributes to the dystrophic phenotype in mdx mice, a Duchenne muscular dystrophy (DMD) model, and that its deletion enhances muscle regeneration by reducing oxidative stress. However, convincing evidence of Dux expression in either intact or injured muscle of wild-type (WT) and mdx mice remains lacking, raising questions about its role in muscle homeostasis. To investigate this, we assessed Dux expression in WT and mdx mice and used Dux knockout (Dux^Δ/Δ) mice to evaluate its function during regeneration following cardiotoxin (CTX)-induced injury. Contrary to prior reports, Dux was not expressed in either WT or mdx mice. Moreover, Dux deletion did not enhance muscle regeneration or affect the expression of the oxidative stress regulator Nrf2 following CTX injury. Lastly, we confirmed that neither DUX4 nor its target genes were induced in muscle biopsies from DMD patients, excluding a role for DUX4 in DMD pathology. Collectively, our results demonstrate that Dux does not impact skeletal muscle regeneration or DUX4 contribution to the DMD dystrophic phenotype, directly challenging the conclusions of a previously published study. We comment on issues of editorial oversight that led to the publication of that study and highlight the deleterious impact of the growing wave of fraudulent publications. Full article

Extracellular vesicles (EVs) are membrane-bound structures released by cells carrying diverse biomolecules involved in intercellular communication. Small EVs are abundant in body fluids, playing a key role in cell signaling. Their natural occurrence and therapeutic potential, especially in the context of muscular disorders, make them a significant area of research. Sarcopenia, characterized by progressive muscle fiber loss, represents a pathological state in which EVs could offer therapeutic benefits, reducing morbidity and mortality. Recent studies have proposed an interplay between adipose tissue (AT) and skeletal muscle regarding sarcopenia pathology. AT dysregulation, as seen in obesity, contributes to skeletal muscle loss in a multifactorial way. While AT-derived stem cell (ATDSC) small EVs have been implicated in musculoskeletal homeostasis, their precise action in muscle regeneration remains incompletely understood. In this context, ATDSC-derived small EVs can stimulate skeletal muscle regeneration through improved proliferation and migration of muscle cells, enhancement of muscular perfusion, improvement of tendon and nerve regeneration, stimulation of angiogenesis, and promotion of myogenic differentiation. However, they can also increase skeletal muscle loss. Notably, this is the first comprehensive review to systematically examine the role of ATDSC-derived small EVs in sarcopenia. Full article